Guanidine and amidine derivatives as factor Xa inhibitors

ABSTRACT

The present invention relates to compounds of the formula I,  
                 
 
     in which R 0 ; Q; X; Q′, D, R 10  and V have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

[0001] The present invention relates to compounds of the formula I,

[0002] in which R₀; Q; X; Q′, D, R₁₀ and V have the meanings indicatedbelow. The compounds of the formula I are valuable pharmacologicallyactive compounds. They exhibit a strong antithrombotic effect and aresuitable, for example, for the therapy and prophylaxis of cardiovasculardisorders like thromboembolic diseases or restenoses. They arereversible inhibitors of the blood clotting enzymes factor Xa (FXa)and/or factor VIIa (FVIIa), and can in general be applied in conditionsin which an undesired activity of factor Xa and/or factor VIIa ispresent or for the cure or prevention of which an inhibition of factorXa and/or factor VIIa is intended. The invention furthermore relates toprocesses for the preparation of compounds of the formula I, their use,in particular as active ingredients in pharmaceuticals, andpharmaceutical preparations comprising them.

[0003] Normal haemeostasis is the result of a complex balance betweenthe processes of clot initiation, formation and clot dissolution. Thecomplex interactions between blood cells, specific plasma proteins andthe vascular surface, maintain the fluidity of blood unless injury andblood loss occurs (EP-A-987274). Many significant disease states arerelated to abnormal haemostasis. For example, local thrombus formationdue to rupture of atheroslerotic plaque is a major cause of acutemyocardial infarction and unstable angina. Treatment of an occlusivecoronary thrombus by either thrombolytic therapy or percutaneousangioplasty may be accompanied by acute thrombolytic reclosure of theaffected vessel.

[0004] There continues to be a need for safe and effective therapeuticanticoagulants to limit or prevent thrombus formation. It is mostdesirable to develop agents that inhibit coagulation without directlyinhibiting thrombin but by inhibiting other steps in the coagulationcascade like factor Xa and/or factor VIIa activity. It is now believedthat inhibitors of factor Xa carry a lower bleeding risk than thrombininhibitors (A. E. P. Adang & J. B. M. Rewinkel, Drugs of the Future2000, 25, 369-383).

[0005] Low molecular weight, factor Xa-specific blood clottinginhibitors that are effective but do not cause unwanted side effectshave been described, for example, in WO-A-95/29189. However, besidesbeing an effective factor Xa-specific blood clotting inhibitor, it isdesirable that such inhibitors also have further advantageousproperties, for instance stability in plasma and liver and selectivityversus other serine proteases whose inhibition is not intended, such asthrombin. There is an ongoing need for further low molecular weightfactor Xa specific blood clotting inhibitors which are effective andhave the above advantages as well.

[0006] Specific inhibition of the factor VIIa/tissue factor catalyticcomplex using monoclonal antibodies (WO-A-92/06711) or a protein such aschloromethyl ketone inactivated factor VIIa (WO-A-96/12800,WO-A-97/47651) is an extremely effective means of controlling thrombusformation caused by acute arterial injury or the thromboticcomplications related to bacterial septicemia. There is alsoexperimental evidence suggesting that inhibition of factor VIIa/tissuefactor activity inhibits restenosis following balloon angioplasty.Bleeding studies have been conducted in baboons and indicate thatinhibition of the factor VIIa/tissue factor complex has the widestsafety window with respect to therapeutic effectiveness and bleedingrisk of any anticoagulant approach tested including thrombin, plateletand factor Xa inhibition. Certain inhibitors of factor VIIa have alreadybeen described. EP-A-987274, for example discloses compounds containinga tripeptide unit which inhibit factor VIIa. However, the propertyprofile of these compounds is still not ideal, and there is an ongoingneed for further low molecular weight factor VIIa inhibitory bloodclotting inhibitors.

[0007] The present invention satisfies the above needs by providingnovel compounds of the formula I which exhibit factor Xa and/or factorVIIa inhibitory activity and are favorable agents for inhibitingunwanted blood clotting and thrombus formation.

[0008] Thus, the present invention relates to compounds of the formulaI,

[0009] wherein

[0010] R₀ is

[0011] 1. phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R² or

[0012] 2. a mono- or bicyclic 5- to 10-membered heteroaryl containingone or two nitrogen atoms as ring heteroatoms, wherein heteroaryl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R²,

[0013] R² is

[0014] 1. —NO₂,

[0015] 2. halogen,

[0016] 3. —CN,

[0017] 4. —OH,

[0018] 5. —NH₂,

[0019] 6. (C₁-C₈)-alkyloxy-, wherein alkyloxy is unsubstituted or mono-,di- or trisubstituted independently of one another by halogen, aminogroup, hydroxy group or methoxy group, or

[0020] 7. —(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by halogen, amino group,hydroxy group or methoxy group,

[0021] Q and Q′ are independently of one another identical or differentand are a direct bond, —O—, —S—, —NR¹⁰—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —S(O)—,—SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰-oder —C(O)—;

[0022] R¹⁰ is hydrogen atom or (C₁-C₄)-alkyl-,

[0023] X is

[0024] 1. a direct bond,

[0025] 2. (C₁-C₆)-alkylen, wherein alkylen is unsubstituted or mono-,di- or trisubstituted independently of one another by halogen, aminogroup or hydroxy group,

[0026] 3. (C₃-C₆)-cycloalkylen, wherein cycloalkylen is unsubstituted ormono-, di- or trisubstituted independently of one another by halogen,amino group or hydroxy group,

[0027] provided that at least one of Q, X and Q′ is not a direct bond,

[0028] D is an atom out of the group carbon, oxygen, sulfur andnitrogen, the substructure of formula III

[0029] is

[0030] 1. a mono- or bicyclic 5- to 10-membered carbocyclic aryl group,wherein said 5- to 10-membered carbocyclic aryl group is unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹,

[0031] 2. phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹,

[0032] 3. a mono- or bicyclic 5-to 10-membered heterocyclic group (Het),containing one or more heteroatoms as ring heteroatoms, such asnitrogen, sulfur or oxygen, wherein said Het group is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹, or

[0033] 4. pyridyl, wherein pyridyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹,

[0034] R¹ is

[0035] 1. halogen,

[0036] 2. —NO₂,

[0037] 3. —CN,

[0038] 4. R¹¹R¹²N—, wherein R¹¹R¹² independently of one another arehydrogen atom, (C₁-C₄)-alkyl- or (C₁-C₆)-acyl-,

[0039] 5. (C₁-C₈)-alkylamino-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0040] 6. —OH,

[0041] 7. —SO₂—NH₂,

[0042] 8. (C₁-C₈)-alkyloxy-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0043] 9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,

[0044] 10 (C₁-C₈)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³,

[0045] 11. hydroxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,

[0046] 12. (C₁-C₈)-alkyloxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkylis unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,

[0047] 13. (C₁-C₈)-alkylsulfonyl-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, or

[0048] 14. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one anotherare hydrogen atom or (C₁-C₄)-alkyl-, or

[0049] two R¹ residues bonded to adjacent ring carbon atoms togetherwith the carbon atoms to which they are bonded form an aromatic ringcondensed to the ring depicted in formula I, where the ring formed bythe two R¹ residues is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³, or

[0050] R¹¹ and R¹² together with the nitrogen atom to which they arebonded form a saturated or unsaturated 5- to 6-membered monocyclicheterocyclic ring which in addition to the nitrogen atom carrying R¹¹and R¹² can contain one or two identical or different ring heteroatomschosen from oxygen, sulfur and nitrogen, and in which one or two of thering carbon atoms can be substituted by oxo to form —C(O)— residue(s),

[0051] R¹³ is

[0052] 1. halogen,

[0053] 2. —NO₂,

[0054] 3. —CN,

[0055] 4. —OH,

[0056] 5. (C₁-C₈)-alkyl-,

[0057] 6. (C₁-C₈)-alkyloxy-,

[0058] 7. —CF₃ or

[0059] 8. —NH₂,

[0060] V is a residue of the formulae IIa, IIb, IIc, IId, IIe or IIf,

[0061] wherein

[0062] L is is a direct bond or (C₁-C₃)-alkylene, wherein alkylene isunsubstituted or mono-, di- or trisubstituted independently of oneanother by A,

[0063] A is

[0064] 1. hydrogen atom,

[0065] 2. —C(O)—OH,

[0066] 3. —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by —OH, —NH₂or —(C₁-C₄)-alkoxy,

[0067] 4. —C(O)—NR⁴R⁵,

[0068] 5. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by —OH, —NH₂ or—(C₁-C₄)-alkoxy,

[0069] 6. —SO₂—NH₂ or

[0070] 7. —SO₂—CH₃,

[0071] U is —NH₂, (C₁-C₄)-alkyl-,—NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(C₁-C₄)-alkyl-aryl,

[0072] M is hydrogen atom, (C₁-C₃)-alkyl- or —OH,

[0073] R⁴ and R⁵ are independently of one another identical or differentand are

[0074] 1. hydrogen atom,

[0075] 2. (C₁-C₁₂)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³ as defined above,

[0076] 3. (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and aryl areunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³ as defined above,

[0077] 4. (C₆-C₁₄)-aryl-, wherein aryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³ as defined above,

[0078] 5. Het-, wherein Het- is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³ as defined above, or

[0079] 6. Het-(C₁-C₄)-alkyl-, wherein alkyl and Het- are unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹³ asdefined above, or

[0080] R⁴ and R⁵ together with the nitrogen atom to which they arebonded form a saturated 3- to 8-membered monocyclic heterocyclic ringwhich in addition to the nitrogen atom carrying R⁴ and R⁵ can containone or two identical or different ring heteroatoms chosen from oxygen,sulfur and nitrogen;

[0081] in all its stereoisomeric forms and mixtures thereof in anyratio, and its physiologically tolerable salts.

[0082] Preferred are compounds of the formula 1, wherein

[0083] R₀ is phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R², or

[0084] pyridyl, wherein pyridyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R²,

[0085] R² is

[0086] 1. —NO₂,

[0087] 2. halogen,

[0088] 3. —CN,

[0089] 4. —OH,

[0090] 5. —NH₂,

[0091] 6. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted or mono-,di- or trisubstituted independently of one another by halogen, aminogroup, hydroxy group or methoxy group, or

[0092] 7. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by halogen, amino group,hydroxy group or methoxy group,

[0093] Q, Q′, X, R¹, R¹¹ and R¹² are as defined above,

[0094] D is an atom out of the group carbon and nitrogen,

[0095] the substructure of formula III is

[0096] 1. phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹, or

[0097] 2. pyridyl, wherein pyridyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹,

[0098] R¹³ is

[0099] 1. halogen,

[0100] 2. —NO₂,

[0101] 3. —CN,

[0102] 4. —OH,

[0103] 5. (C₁-C₄)-alkyl-,

[0104] 6. (C₁-C₄)-alkyloxy-,

[0105] 7. —CF₃ or

[0106] 8. —NH₂,

[0107] R₁₀ is hydrogen atom or methyl,

[0108] V is a fragment of the formula IIa, IIb, IIc, IId, IIe or IIf asdefined above, wherein

[0109] L, U, M, R⁴ and R⁵ are as defined above, and

[0110] A is

[0111] 1. hydrogen atom,

[0112] 2. —C(O)—OH,

[0113] 3. —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by —OH, —NH₂or —(C₁-C₄)-alkoxy,

[0114] 4. —C(O)—NR⁴R⁵ or

[0115] 5. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by —OH, —NH₂ or—(C₁-C₄)-alkoxy.

[0116] More preferred are compounds of the formula 1, wherein

[0117] R₀ is phenyl, wherein phenyl is mono-, di- or trisubstitutedindependently of one another by R², or

[0118] pyridyl, wherein pyridyl is mono-, di- or trisubstitutedindependently of one another by R²,

[0119] R²is

[0120] 1. —NH₂,

[0121] 2. halogen,

[0122] 3. —CN,

[0123] 4. —OH,

[0124] 5. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted orsubstituted by an amino group, or

[0125] 6. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or substitutedby an amino group,

[0126] Q and Q′ are independently of one another identical or differentand are a direct bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—; or—SO₂—NR¹⁰—;

[0127] X is

[0128] 1. a direct bond or

[0129] 2. (C₁-C₄)-alkylen, wherein alkylen is unsubstituted or mono-,di- or trisubstituted independently of one another by halogen, aminogroup or hydroxy group,

[0130] D is an atom out of the group carbon and nitrogen,

[0131] the substructure of formula III is

[0132] phenyl or pyridyl, wherein phenyl and pyridyl are unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹,

[0133] R¹ is

[0134] 1. halogen,

[0135] 2. —NO₂,

[0136] 3. —CN,

[0137] 4. —NH₂,

[0138] 5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0139] 6. —OH,

[0140] 7. —SO₂—NH₂,

[0141] 8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0142] 9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,

[0143] 10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³,

[0144] 11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³,

[0145] 12. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one anotherare hydrogen atom or (C₁-C₄)-alkyl-,

[0146] 13. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above, or

[0147] 14. —NR⁴R⁵,

[0148] R¹³ is

[0149] 1. halogen,

[0150] 2. —NO₂,

[0151] 3. —CN,

[0152] 4. —OH,

[0153] 5. (C₁-C₄)-alkyl-,

[0154] 6. (C₁-C₄)-alkyloxy-,

[0155] 7. —CF₃ or

[0156] 8. —NH₂,

[0157] R₁₀ is hydrogen atom or methyl,

[0158] V is a fragment of the formula IIa, IIb, IIc, IId, IIe or IIf asdefined above, wherein

[0159] L is a direct bond or (C₁-C₃)-alkylen-,

[0160] A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵or (C₁-C₄)-alkyl,

[0161] U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(CH₂)-phenyl,

[0162] M is hydrogen atom, (C₁-C₃)-alkyl- or —OH, and

[0163] R⁴ and R⁵ are independently of one another hydrogen atom or(C₁-C₄)-alkyl-.

[0164] Even more preferred are the compounds of the formula I, wherein

[0165] R₀ is phenyl or pyridyl, wherein phenyl and pyridyl independentlyfrom one another are mono-, di- or trisubstituted independently of oneanother by R²,

[0166] R² is

[0167] 1. halogen,

[0168] 2. —CN,

[0169] 3. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted orsubstituted by halogen or an amino group, or

[0170] 4. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or substitutedby an amino group or halogen,

[0171] Q and Q′ are independently of one another identical or differentand are a direct bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—; or—SO₂—NR¹⁰—;

[0172] X is —(C₁-C₃)-alkylen-, wherein alkylen is unsubstituted ormono-, di- or trisubstituted independently of one another by halogen,amino group or hydroxy group,

[0173] D is the atom carbon,

[0174] the substructure of formula III is

[0175] phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹,

[0176] R¹ is

[0177] 1. halogen,

[0178] 2. —NO₂,

[0179] 3. —CN,

[0180] 4. —NH₂,

[0181] 5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0182] 6. —OH,

[0183] 7. —SO₂—NH₂,

[0184] 8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0185] 9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,

[0186] 10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³,

[0187] 11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³,

[0188] 12. —C(O)—NR⁴R⁵, wherein R¹⁴R¹⁵ independently of one another arehydrogen atom or (C₁-C₄)-alkyl-,

[0189] 13. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above, or

[0190] 14. —NR⁴R⁵, wherein R⁴ and R⁵ are independently of one anotherhydrogen atom or methyl

[0191] R is

[0192] 1. halogen,

[0193] 2. —CF₃,

[0194] 3. —NH₂,

[0195] 4. —OH,

[0196] 5. (C₁-C₄)-alkyl- or

[0197] 6. (C₁-C₄)-alkyloxy-,

[0198] R₁₀ is hydrogen atom, and

[0199] V is a fragment of the formula IIa, IIb, IIc or IId as definedabove, wherein

[0200] L is a direct bond or (C₁-C₂)-alkylen-,

[0201] A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵or (C₁-C₄)-alkyl,

[0202] U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(CH₂)-phenyl,

[0203] M is hydrogen atom or (C₁-C₃)-alkyl-.

[0204] Further preferred are compounds of the formula 1, wherein

[0205] R₀ is phenyl, wherein phenyl is mono-, di- or trisubstitutedindependently of one another by R²,

[0206] R² is

[0207] 1. halogen,

[0208] 2. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted orsubstituted by halogen or an amino group, or

[0209] 3. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or substitutedby an amino group or halogen,

[0210] Q and Q′ are independently of one another identical or differentand are a direct bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—; or—SO₂—NR¹⁰—;

[0211] X is —(C₁-C₃)-alkylen-,

[0212] D is the atom carbon,

[0213] the substructure of formula III is

[0214] phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹,

[0215] R¹ is

[0216] 1. halogen,

[0217] 2. —NO₂,

[0218] 3. —CN,

[0219] 4. —NH₂,

[0220] 5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0221] 6. —OH,

[0222] 7. —SO₂—NH₂,

[0223] 8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,

[0224] 9. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³,

[0225] 10. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³,

[0226] 11. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one anotherare hydrogen atom or (C₁-C₂)-alkyl-,

[0227] 12. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above, or

[0228] 13. —NR⁴R⁵,

[0229] R¹³ is

[0230] 1. halogen,

[0231] 2. —CF₃,

[0232] 3. —NH₂,

[0233] 4. —OH,

[0234] 5. (C₁-C₄)-alkyl- or

[0235] 6. (C₁-C₄)-alkyloxy-,

[0236] R₁₀ is hydrogen atom, and

[0237] V is a fragment of the formula IIa, IIb, IIc or IId as definedabove, wherein

[0238] L is a direct bond or (C₁-C₂)-alkylen-,

[0239] A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵or —(C₁-C₄)-alkyl,

[0240] U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(CH₂)-phenyl,

[0241] M is hydrogen atom or methyl, and

[0242] R⁴ and R⁵ are independently of one another hydrogen atom ormethyl.

[0243] Particularly preferred are compounds of the formula I, wherein

[0244] R₀ is phenyl, wherein phenyl is disubstituted independently ofone another by R²,

[0245] R² is

[0246] 1. halogen,

[0247] 2. (C₁-C₂)-alkyloxy-, wherein alkyloxy is unsubstituted orsubstituted by an amino group, or

[0248] 3. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or substitutedby an amino group,

[0249] Q and Q′ are independently of one another identical or differentand are a direct bond or —O—,

[0250] X is —CH₂—CH₂—,

[0251] D is the atom carbon,

[0252] the substructure of formula III is

[0253] phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹,

[0254] R¹ is

[0255] 1. halogen,

[0256] 2. —OH,

[0257] 3. —NH₂,

[0258] 4. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one another arehydrogen atom or (C₁-C₂)-alkyl-,

[0259] 5. (C₁-C₃)-alkyloxy-, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³, or

[0260] 6. (C₁-C₃)-alkyl-, wherein alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³,

[0261] R¹³ is fluorine or chlorine,

[0262] R₁₀ is hydrogen atom, and

[0263] V is a fragment of the formula IIa, IIb, IIc or IId as definedabove, wherein

[0264] L is a direct bond or (C₁-C₂)-alkylen-,

[0265] A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵or —(C₁-C₄)-alkyl,

[0266] U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(CH₂)-phenyl,

[0267] M is hydrogen atom, and

[0268] R⁴ and R⁵ are independently of one another hydrogen atom ormethyl.

[0269] In general, the meaning of any group, residue, heteroatom, numberetc. which can occur more than once in the compounds of the formula I,is independent of the meaning of this group, residue, heteroatom, numberetc. in any other occurrence. All groups, residues, heteroatoms, numbersetc. which can occur more than once in the compounds of the formula Ican be identical or different.

[0270] As used herein, the term alkyl is to be understood in thebroadest sense to mean hydrocarbon residues which can be linear, i.e.straight-chain, or branched and which can be acyclic or cyclic residuesor comprise any combination of acyclic and cyclic subunits. Further, theterm alkyl as used herein expressly includes saturated groups as well asunsaturated groups which latter groups contain one or more, for exampleone, two or three, double bonds and/or triple bonds, provided that thedouble bonds are not located within a cyclic alkyl group in such amanner that an aromatic system results. All these statements also applyif an alkyl group occurs as a substituent on another residue, forexample in an alkyloxy residue, an alkyloxycarbonyl residue or anarylalkyl residue. Examples of alkyl residues containing 1, 2, 3, 4, 5,6, 7 or 8carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl or octyl, the n-isomers of all these residues, isopropyl,isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl,2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl,tert-pentyl, sec-butyl, tert-butyl or tert-pentyl.

[0271] Unsaturated alkyl residues are, for example, alkenyl residuessuch as vinyl, 1-propenyl, 2-propenyl (═allyl), 2-butenyl, 3-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, oralkynyl residues such as ethynyl, 1-propynyl, 2-propynyl (═propargyl) or2-butynyl. Alkyl residues can also be unsaturated when they aresubstituted.

[0272] Examples of cyclic alkyl residues are cycloalkyl residuescontaining 3, 4, 5 or 6 ring carbon atoms like cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, which can also be substituted and/orunsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkylgroups like, for example, cyclopentenyl or cyclohexenyl can be bondedvia any carbon atom.

[0273] Of course, a cyclic alkyl group has to contain at least threecarbon atoms, and an unsaturated alkyl group has to contain at least twocarbon atoms. Thus, a group like (C₁-C₈)-alkyl is to be understood ascomprising, among others, saturated acyclic (C₁-C₈)-alkyl,(C₃-C₆)-cycloalkyl, and unsaturated (C₂-C₈)-alkyl like (C₂-C₈)-alkenylor (C₂-C₈)-alkynyl. Similarly, a group like (C₁-C₄)-alkyl is to beunderstood as comprising, among others, saturated acyclic (C₁-C₄)-alkyl,and unsaturated (C₂-C₄)-alkyl like (C₂-C₄)-alkenyl or (C₂-C₄)-alkynyl.

[0274] Unless stated otherwise, the term alkyl preferably comprisesacyclic saturated hydro-carbon residues which have from one to sixcarbon atoms and which can be linear or branched. A particular group ofsaturated acyclic alkyl residues is formed by (C₁-C₄)-alkyl residueslike methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyland tert-butyl.

[0275] Unless stated otherwise, and irrespective of any specificsubstituents bonded to alkyl groups which are indicated in thedefinition of the compounds of the formula I, alkyl groups can ingeneral be unsubstituted or substituted by one or more, for example one,two or three, identical or different substituents. Any kind ofsubstituents present in substituted alkyl residues can be present in anydesired position provided that the substitution does not lead to anunstable molecule. Examples of substituted alkyl residues are alkylresidues in which one or more, for example 1, 2 or 3, hydrogen atoms arereplaced with halogen atoms, in particular fluorine atoms.

[0276] The term mono- or bicyclic 5- to 10-membered carbocyclic arylgroup refers to for example phenyl or napthyl.

[0277] The term mono- or bicyclic 5- to 10-membered heteroarylcontaining one or two nitrogen atoms as ring heteroatoms refers to(C₅-C₁₀)-aryl in which one or more of the 5 to 10 ring carbon atoms arereplaced by heteroatoms such as nitrogen, oxygen or sulfur. Examples arepyridyl; such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl; such as2-pyrrolyl and 3-pyrrolyl; furyl; such as 2-furyl and 3-furyl; thienyl;such as 2-thienyl and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl,pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl,isoquinolyl or quinoxalinyl.

[0278] The term R¹¹ and R¹² together with the nitrogen atom to whichthey are bonded form a saturated or unsaturated 5- to 6-memberedmonocyclic heterocyclic ring refers to pyrrol, piperidin, pyrrolidine,morpholine, piperazine, pyridine, pyrimidine, imidazole orthiomorpholine.

[0279] The term aryl refers to a monocyclic or polycyclic hydrocarbonresidue in which at least one carbocyclic ring is present that has aconjugated pi electron system. In a (C₆-C₁₄)-aryl residue from 6 to 14ring carbon atoms are present. Examples of (C₆-C₁₄)-aryl residues arephenyl, naphthyl, biphenylyl, fluorenyl or anthracenyl. Unless statedotherwise, and irrespective of any specific substituents bonded to arylgroups which are indicated in the definition of the compounds of theformula I, aryl residues, for example phenyl, naphthyl or fluorenyl, canin general be unsubstituted or substituted by one or more, for exampleone, two or three, identical or different substituents. Aryl residuescan be bonded via any desired position, and in substituted aryl residuesthe substituents can be located in any desired position.

[0280] Unless stated otherwise, and irrespective of any specificsubstituents bonded to aryl groups which are indicated in the definitionof the compounds of the formula 1, substituents that can be present insubstituted aryl groups are, for example, (C₁-C₈)-alkyl, in particular(C₁-C₄)-alkyl, such as methyl, ethyl or tert-butyl, hydroxy,(C₁-C₈)-alkyloxy, in particular (C₁-C₄)-alkyloxy, such as methoxy,ethoxy or tert-butoxy, methylenedioxy, ethylenedioxy, F, Cl, Br, I,cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl, formyl,acetyl, amino, mono- or di-(C₁-C₄)-alkylamino,((C₁-C₄)-alkyl)carbonylamino like acetylamino, hydroxycarbonyl,((C₁-C₄)-alkyloxy)carbonyl, carbamoyl, benzyl optionally substituted inthe phenyl group, optionally substituted phenyl, optionally substitutedphenoxy or benzyloxy optionally substituted in the phenyl group. Asubstituted aryl group which is present in a specific position of thecompounds of formula I can independently of other aryl groups besubstituted by substituents selected from any desired subgroup of thesubstituents listed before and/or in the specific definition of thatgroup. For example, a substituted aryl group may be substituted by oneor more identical or different substituents chosen from (C₁-C₄)-alkyl,hydroxy, (C₁-C₄)-alkyloxy, F, Cl, Br, I, cyano, nitro, trifluoromethyl,amino, phenyl, benzyl, phenoxy and benzyloxy. In general, preferably notmore than two nitro groups are present in the compounds of the formulaI.

[0281] In monosubstituted phenyl residues the substituent can be locatedin the 2-position, the 3-position or the 4-position, with the 3-positionand the 4-position being preferred. If a phenyl group carries twosubstituents, they can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenylresidues carrying three substituents the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position, or 3,4,5-position. Naphthyl residues can be 1-naphthyland 2-naphthyl. In substituted naphthyl residues the substituents can belocated in any positions, for example in monosubstituted 1-naphthylresidues in the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position and inmonosubstituted 2-naphthyl residues in the 1-, 3-, 4-, 5-, 6-, 7-, or8-position. Biphenylyl residues can be 2-biphenylyl, 3-biphenylyl and4-biphenylyl. Fluorenyl residues can be 1-, 2-, 3-, 4- or 9-fluorenyl.In monosubstituted fluorenyl residues bonded via the 9-position thesubstituent is preferably present in the 1-, 2-, 3- or 4-position.

[0282] The group Het comprises groups containing 5, 6, 7, 8, 9 or 10ring atoms in the parent monocyclic or bicyclic heterocyclic ringsystem. In monocyclic groups Het the heterocyclic ring preferably is a5-membered, 6-membered or 7-membered ring, particularly preferably a5-membered or 6-membered ring. In bicyclic groups Het preferably twofused rings are present one of which is a 5-membered ring or 6-memberedheterocyclic ring and the other of which is a 5-membered or 6-memberedheterocyclic or carbocyclic ring, i.e. a bicyclic ring Het preferablycontains 8, 9 or 10 ring atoms, particularly preferably 9 or 10 ringatoms.

[0283] Het comprises saturated heterocyclic ring systems which do notcontain any double bonds within the rings, as well as mono-unsaturatedand poly-unsaturated heterocyclic ring systems which contain one ormore, for example one, two, three, four or five, double bonds within therings provided that the resulting system is stable. Unsaturated ringsmay be non-aromatic or aromatic, i.e. double bonds within the rings inthe group Het may be arranged in such a manner that a conjugated pielectron system results.

[0284] Aromatic rings in a group Het may be 5-membered or 6-memberedrings, i.e. aromatic groups in a group Het contain 5 to 10 ring atoms.Aromatic rings in a group Het thus comprise 5-membered and 6-memberedmonocyclic heterocycles and bicyclic heterocycles composed of two5-membered rings, one 5-membered ring and one 6-membered ring, or two6-membered rings. In bicyclic aromatic groups in a group Het one or bothrings may contain heteroatoms. Aromatic groups Het may also be referredto by the customary term heteroaryl for which all the definitions andexplanations above and below relating to Het correspondingly apply.

[0285] Unless stated otherwise, in the groups Het and any otherheterocyclic groups preferably 1, 2, 3 or 4 identical or different ringheteroatoms chosen from nitrogen, oxygen and sulfur are present.Particularly preferably in these groups one or two identical ordifferent heteroatoms chosen from nitrogen, oxygen and sulfur arepresent. The ring heteroatoms can be present in any desired number andin any position with respect to each other provided that the resultingheterocyclic system is known in the art and is stable and suitable as asubgroup in a drug substance. Examples of parent structures ofheterocycles from which the group Het can be derived are aziridine,oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole,pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, pyridine, pyran, thiopyran, pyridazine,pyrimidine, pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine,1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,1,3-benzodioxole, indazole, benzimidazole, benzoxazole, benzothiazole,quinoline, isoquinoline, chromane, isochromane, cinnoline, quinazoline,quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines,pyridopyrimidines, purine, pteridine etc. as well as ring systems whichresult from the listed heterocycles by fusion (or condensation) of acarbocyclic ring, for example benzo-fused, cyclopenta-fused,cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.

[0286] The fact that many of the before-listed names of heterocycles arethe chemical names of unsaturated or aromatic ring systems does notimply that the groups Het could only be derived from the respectiveunsaturated ring system. The names here only serve to describe the ringsystem with respect to ring size and the number of the heteroatoms andtheir relative positions. As explained above, the group Het can besaturated or partially unsaturated or aromatic, and can thus be derivednot only from the before-listed heterocycles themselves but also fromall their partially or completely hydrogenated analogues and also fromtheir more highly unsaturated analogues if applicable. As examples ofcompletely or partially hydrogenated analogues of the before-listedheterocycles from which the groups Het may be derived the following maybe mentioned: pyrroline, pyrrolidine, tetrahydrofuran,tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine,1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro -1,3-oxazol,1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine,perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine (=morpholine),perhydro-1,4-thiazine (=thiomorpholine), perhydroazepine, indoline,isoindoline, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, etc.

[0287] The residue Het may be bonded via any ring carbon atom, and inthe case of nitrogen heterocycles via any suitable ring nitrogen atom.Thus, for example, a pyrrolyl residue can be 1-pyrrolyl, 2-pyrrolyl or3-pyrrolyl, a pyrrolidinyl residue can be pyrrolidin-1-yl(═pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, a pyridinyl residuecan be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, a piperidinyl residuecan be piperidin-1-yl (═piperidino), piperidin-2-yl, piperidin-3-yl orpiperidin-4-yl. Furyl can be 2-furyl or 3-furyl, thienyl can be2-thienyl or 3-thienyl, imidazolyl can be imidazol-1-yl, imidazol-2-yl,imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be 1,3-oxazol-2-yl,1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl canbe pyrimidin-2-yl, pyrimidin-4-yl (═6-pyrimidinyl) or 5-pyrimidinyl,piperazinyl can be piperazin-1-yl (═piperazin-4-yl ═piperazino) orpiperazin-2-yl. Indolyl can be indol-1-yl, indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl. Similarlybenzimidazolyl, benzoxazolyl and benzothiazol residues can be bonded viathe 2-position and via any of the positions 4, 5, 6, and 7. Quinolinylcan be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl,quinolin-6-yl, quinolin-7-yl or quinolin-8-yl, isoqinolinyl can beisoquinol-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl,isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl. In addition tobeing bonded via any of the positions indicated for quinolinyl andisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl and1,2,3,4-tetrahydroisoquinolinyl can also be bonded via the nitrogenatoms in 1-position and 2-position, respectively.

[0288] Unless stated otherwise, and irrespective of any specificsubstituents bonded to groups Het or any other heterocyclic groups whichare indicated in the definition of the compounds of the formula I, thegroup Het can be unsubstituted or substituted on ring carbon atoms withone or more, for example one, two, three, four or five, identical ordifferent substituents like (C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl,(C₁-C₈)-alkyloxy, in particular (C₁-C₄)-alkyloxy, (C₁-C₄)-alkylthio,halogen, nitro, amino, ((C₁-C₄)-alkyl)carbonylamino like acetylamino,trifluoromethyl, trifluoromethoxy, hydroxy, oxo, hydroxy-(C₁-C₄)-alkylsuch as, for example, hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl,methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, aminosulfonyl,methylsulfonyl, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkyloxycarbonyl, optionally substituted phenyl, optionallysubstituted phenoxy, benzyl optionally substituted in the phenyl group,benzyloxy optionally substituted in the phenyl group, etc. Thesubstituents can be present in any desired position provided that astable molecule results. Of course an oxo group cannot be present in anaromatic ring. Each suitable ring nitrogen atom in a group Het canindependently of each other be unsubstituted, i.e. carry a hydrogenatom, or can be substituted, i.e. carry a substituent like(C₁-C₈)-alkyl, for example (C₁-C₄)-alkyl such as methyl or ethyl,optionally substituted phenyl, phenyl-(C₁-C₄)-alkyl, for example benzyl,optionally substituted in the phenyl group, hydroxy-(C₂-C₄)-alkyl suchas, for example 2-hydroxyethyl, acetyl or another acyl group,methylsulfonyl or another sulfonyl group, aminocarbonyl,(C₁-C₄)-alkyloxycarbonyl, etc. In general, in the compounds of theformula I nitrogen heterocycles can also be present as N-oxides or asquaternary salts. Ring sulfur atoms can be oxidized to the sulfoxide orto the sulfone. Thus, for example a tetrahydrothienyl residue may bepresent as S,S-dioxotetrahydrothienyl residue or a thiomorpholinylresidue like thiomorpholin-4-yl may be present as1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl. A substitutedgroup Het that can be present in a specific position of the compounds offormula I can independently of other groups Het be substituted bysubstituents selected from any desired subgroup of the substituentslisted before and/or in the definition of that group.

[0289] Halogen is fluorine, chlorine, bromine or iodine, preferablyfluorine, chlorine or bromine, particularly preferably chlorine orbromine.

[0290] Optically active carbon atoms present in the compounds of theformula I can independently of each other have R configuration or Sconfiguration. The compounds of the formula I can be present in the formof pure enantiomers or pure diastereomers or in the form of mixtures ofenantiomers and/or diastereomers, for example in the form of racemates.The present invention relates to pure enantiomers and mixtures ofenantiomers as well as to pure diastereomers and mixtures ofdiastereomers. The invention comprises mixtures of two or of more thantwo stereoisomers of the formula I, and it comprises all ratios of thestereoisomers in the mixtures. In case the compounds of the formula Ican be present as E isomers or Z isomers (or cis isomers or transisomers) the invention relates both to pure E isomers and pure Z isomersand to E/Z mixtures in all ratios. The invention also comprises alltautomeric forms of the compounds of the formula I.

[0291] Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallization of diastereomeric salts obtained with optically activeacids or bases. Stereochemically unifom compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

[0292] The choice of incorporating into a compound of the formula I abuilding block with R configuration or S configuration, or in the caseof an amino acid unit present in a compound of the formula I ofincorporating a building block designated as D-amino acid or L-aminoacid, can depend, for example, on the desired characteristics of thecompound of the formula I. For example, the incorporation of a D-aminoacid building block can confer increased stability in vitro or in vivo.The incorporation of a D-amino acid building block also can achieve adesired increase or decrease in the pharmacological activity of thecompound. In some cases it can be desirable to allow the compound toremain active for only a short period of time. In such cases, theincorporation of an L-amino acid building block in the compound canallow endogenous peptidases in an individual to digest the compound invivo, thereby limiting the individual's exposure to the active compound.A similar effect may also be observed in the compounds of the inventionby changing the configuration in another building block from Sconfiguration to R configuration or vice versa. By taking intoconsideration the medical needs one skilled in the art can determine thedesirable characteristics, for example a favorable stereochemistry, ofthe required compound of the invention.

[0293] Physiologically tolerable salts of the compounds of formula I arenontoxic salts that are physiologically acceptable, in particularpharmaceutically utilizable salts. Such salts of compounds of theformula I containing acidic groups, for example a carboxy group COOH,are for example alkali metal salts or alkaline earth metal salts such assodium salts, potassium salts, magnesium salts and calcium salts, andalso salts with physiologically tolerable quarternary ammonium ions suchas tetramethylammonium or tetraethylammonium, and acid addition saltswith ammonia and physiologically tolerable organic amines, such asmethylamine, dimethylamine, trimethylamine, ethylamine, triethylamine,ethanolamine or tris-(2-hydroxyethyl)amine. Basic groups contained inthe compounds of the formula 1, for example amino groups or guanidinogroups, form acid addition salts, for example with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid orphosphoric acid, or with organic carboxylic acids and sulfonic acidssuch as formic acid, acetic acid, oxalic acid, citric acid, lactic acid,malic acid, succinic acid, malonic acid, benzoic acid, maleic acid,fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonicacid. Compounds of the formula I which simultaneously contain a basicgroup and an acidic group, for example a guanidino group and a carboxygroup, can also be present as zwitterions (betaines) which are likewiseincluded in the present invention.

[0294] Salts of compounds of the formula I can be obtained by customarymethods known to those skilled in the art, for example by combining acompound of the formula I with an inorganic or organic acid or base in asolvent or dispersant, or from other salts by cation exchange or anionexchange. The present invention also includes all salts of the compoundsof the formula I which, because of low physiologically tolerability, arenot directly suitable for use in pharmaceuticals but are suitable, forexample, as intermediates for carrying out further chemicalmodifications of the compounds of the formula I or as starting materialsfor the preparation of physiologically tolerable salts. The presentinvention furthermore includes all solvates of compounds of the formulaI, for example hydrates or adducts with alcohols.

[0295] The invention also includes derivatives and modifications of thecompounds of the formula I, for example prodrugs, protected forms andother physiologically tolerable derivatives, as well as activemetabolites of the compounds of the formula I. The invention relates inparticular to prodrugs and protected forms of the compounds of theformula I which can be converted into compounds of the formula I underphysiological conditions. Suitable prodrugs for the compounds of theformula I, i.e. chemically modified derivatives of the compounds of theformula I having properties which are improved in a desired manner, forexample with respect to solubility, bioavailability or duration ofaction, are known to those skilled in the art. More detailed informationrelating to prodrugs is found in standard literature like, for example,Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985,, Fleisher etal., Advanced Drug Delivery Reviews 19 (1996) 115-130; or H. Bundgaard,Drugs of the Future 16 (1991) 443 which are all incorporated herein byreference. Suitable prodrugs for the compounds of the formula I areespecially acyl prodrugs and carbamate prodrugs of acylatablenitrogen-containing groups such as amino groups and the guanidino groupand also ester prodrugs and amide prodrugs of carboxylic acid groupswhich may be present in compounds of the formula I. In the acyl prodrugsand carbamate prodrugs one or more, for example one or two, hydrogenatoms on nitrogen atoms in such groups are replaced with an acyl groupor a carbamate, preferably a (C₁-C₆)-alkyloxycarbonyl group. Suitableacyl groups and carbamate groups for acyl prodrugs and carbamateprodrugs are, for example, the groups R^(p1)—CO— and R^(p2)O—CO—, inwhich R_(p1) is hydrogen, (C₁-C₁₈)-alkyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl-, (C₆-C₁₄)-aryl, Het-,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- or Het-(C₁-C₄)-alkyl- and in which R^(p2)has the meanings indicated for R^(p1) with the exception of hydrogen.

[0296] A further embodiement of the present invention are prodrugs ofthe compounds of the formula 1, preferably (C₁-C₆)-acyl prodrugs and(C₁-C₆)-alkyloxycarbonyl prodrugs.

[0297] The present invention also relates to processes of preparation bywhich the compounds of the formula I are obtainable and which comprisecarrying out one or more of the synthesis steps described below. Thecompounds of the formula I can generally be prepared, for example in thecourse of a convergent synthesis, by linkage of two or more fragmentswhich can be derived retrosynthetically from the formula 1. In thecourse of the preparation of the compounds of the formula I it cangenerally be advantageous or necessary to introduce functional groupswhich could lead to undesired reactions or side reactions in therespective synthesis step, in the form of precursor groups which arelater converted into the desired functional groups, or to temporarilyblock functional groups by a protective group strategy suited to thesynthesis problem. Such strategies are well known to those skilled inthe art (see, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Wiley, 1991). As examples of precursor groups nitro groupsand cyano groups may be mentioned which can later be converted byreduction, for example by catalytic hydrogenation, into amino groups andaminomethyl groups, respectively. Protective groups can also have themeaning of a solid phase, and cleavage from the solid phase stands forthe removal of the protective group. The use of such techniques is knownto those skilled in the art (Burgess K (Ed.) Solid Phase OrganicSynthesis ,New York: Wiley, 2000). For example, a phenolic hydroxy groupcan be attached to a trityl-polystyrene resin, which serves as aprotecting group, and the molecule is cleaved from this resin bytreatment with TFA at a later stage iof the synthesis.

[0298] For example, for the preparation of a compound of the formula Iabuilding block of the formula XI,

[0299] in which R₀, Q, Q′, X, are as defined above for the compounds ofthe formula I but functional groups can optionally also be present inthe form of precursor groups or can be protected by protective groupsknown to those skilled in the art, e.g. an amino group can be protectedwith a tert.-butyloxycarbonyl group or a benzyloxycarbonyl group.R^(1′), R^(1″), R^(1′″), R^(1″″), are defined as hydrogen or as R¹ whichhas the same meaning as in formula I but can optionally also be presentin the form of precursor groups or can be protected by protective groupsknown to those skilled in the art, e.g. a hydroxy group may be attachedto a polystyrene resin, and Y is a nucleophilically substituable leavinggroup or a hydroxyl group, is reacted with a fragment of the formula III

H—NR₁₀—V  (XII)

[0300] in which R₁₀ and V are as defined above for the compounds of theformula I but functional groups can optionally also be present in theform of precursor groups or can be protected by protective groups.

[0301] The group COY in the formula XI is preferably the carboxylic acidgroup COOH or an activated carboxylic acid derivative. Y can thus be,for example, hydroxyl, halogen, in particular chlorine or bromine,alkoxy, in particular methoxy or ethoxy, aryloxy, for example phenoxy orpentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a residueof a nitrogen heterocycle bonded via a nitrogen atom, in particular aresidue of an azole, such as, for example, 1-imidazolyl. Y canfurthermore be, for example, ((C₁-C₄)-alkyl)—O—CO—O— or tolylsulfonyloxyand the activated acid derivative can thus be a mixed anhydride.

[0302] If Y is hydroxyl, then the carboxylic acid is expediently firstactivated, for example by one of the various methods used for peptidecouplings which are well known to those skilled in the art. Examples ofsuitable activation agents are O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU);(König et al., Proc. 21st Europ. Peptide Symp. 1990 (eds. Giralt,Andreu), Escom, Leiden 1991, p. 143),O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (L. A. Carpino, J. Am. Chem. Soc. 1993, 115,4397), or carbodiimides like dicyclohexylcarbodiimide ordiisopropylcarbodiimide. The activation of the carboxylic acid functionmay also favorably be carried, for example, by conversion of thecarboxylic acid group into the pentafluorophenyl ester usingdicyclohexylcarbodiimide and pentafluorophenol. A number of suitablemethods for the preparation of activated carboxylic acid derivatives arealso indicated with details of source literature in J. March, AdvancedOrganic Chemistry, Fourth Edition, John Wiley & Sons, 1992. Theactivation and the subsequent reaction with the compound of the formulaIII are usually carried in the presence of an inert solvent or diluent,for example DCM, chloroform, THF, diethyl ether, n-heptane, n-hexane,n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether,acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl acetate or amixture of these solvents, if appropriate with addition of a base suchas, for example, potassium tert-butoxide or tributylamine ortriethylamine or diisoprpylethylamine.

[0303] The resulting product is a compound of the formula I in whichfunctional groups can also be present in the form of precursor groups orcan be protected by protective groups. If still any protective groups orprecursor groups are present they are then removed by known methods (seeGreene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991),or converted in the desired final groups, respectively. E.g., if acarboxylic acid group protected as tert-butyl ester and the freecarboxylic acid is to be prepared as the final compound the protectivegroup can be removed by reaction with trifluoroacetic acid ortert.-butyloxycarbonyl protecting groups can be removed by treatmentwith trifluoroacetic acid. If desired, with the obtained compoundsfurther reactions can then be carried out by standard processes, forexample acylation reactions or esterification reactions, or thecompounds can be converted into physiologically tolerable salts orprodrugs by standard processes known to those skilled in the art.

[0304] Other compounds of the formula I can be prepared in a similarfashion as described above by coupling of a fragment of the formula XIIIwith fragment XII.

R₀—Q—X—Q′—W—C(O)—Y  (XIII)

[0305] in which R₀, Q, Q′, X and Y are as defined above for thecompounds of the formula I, W is the substructure of formula III, butfunctional groups can optionally also be present in the form ofprecursor groups or can be protected by protective groups known to thoseskilled in the art, e.g. an amino group can be protected with atert.-butyloxycarbonyl group or a benzyloxycarbonyl group or a hydroxygroup may be attached to a polystyrene resin.

[0306] The fragments of the formula XI, XII and XIII are prepared bymethods well known to those skilled in the art (E.g. in J March,Advanced Organic Chemistry, 4^(th) Edition, John Wiley & Sons, 1992; R CLarock, Comprehensive Organic Transformations, VCH Publishers, New York1989).

[0307] The compounds of the present invention are serine proteaseinhibitors which inhibit the activity of the blood coagulation enzymesfactor Xa and/or factor VIIa. In particular, they are highly activeinhibitors of factor Xa. They are specific serine protease inhibitorsinasmuch as they do not substantially inhibit the activity of otherproteases whose inhibition is not desired. The activity of the compoundsof the formula I can be determined, for example, in the assays describedbelow or in other assays known to those skilled in the art. With respectto factor Xa inhibition, a preferred embodiment of the inventioncomprises compounds which have a Ki 1 for factor Xa inhibition asdetermined in the assay described below, with or without concomitantfactor VIIa inhibition, and which preferably do not substantiallyinhibit the activity of other proteases involved in coagulation andfibrinolysis whose inhibition is not desired (using the sameconcentration of the inhibitor). The compounds of the invention inhibitfactor Xa catalytic activity either directly, within the prothrombinasecomplex or as a soluble subunit, or indirectly, by inhibiting theassembly of factor Xa into the prothrombinase complex.

[0308] The present invention also relates to the compounds of theformula I and/or their physiologically tolerable salts and/or theirprodrugs for use as pharmaceuticals (or medicaments), to the use of thecompounds of the formula I and/or their physiologically tolerable saltsand/or their prodrugs for the production of pharmaceuticals forinhibition of factor Xa and/or factor VIIa or for influencing bloodcoagulation, inflammatory response or fibrinolysis or for the therapy orprophylaxis of the diseases mentioned above or below, for example forthe production of pharmaceuticals for the therapy and prophylaxis ofcardiovascular disorders, thromboembolic diseases or restenoses. Theinvention also relates to the use of the compounds of the formula Iand/or their physiologically tolerable salts and/or their prodrugs forthe inhibition of factor Xa and/or factor VIIa or for influencing bloodcoagulation or fibrinolysis or for the therapy or prophylaxis of thediseases mentioned above or below, for example for use in the therapyand prophylaxis of cardiovascular disorders, thromboembolic diseases orrestenoses, and to methods of treatment aiming at such purposesincluding methods for said therapies and prophylaxis. The presentinvention also relates to pharmaceutical preparations (or pharmaceuticalcompositions) which contain an effective amount of at least one compoundof the formula I and/or its physiologically tolerable salts and/or itsprodrugs in addition to a customary pharmaceutically acceptable carrier,i.e. one or more pharmaceutically acceptable carrier substances orexcipients and/or auxiliary substances or additives.

[0309] Preferred are the treatment of disease states such as abnormalthrombus formation, acute myocardial infarction, unstable angina,thromboembolism, acute vessel closure associated with thrombolytictherapy or percutaneous transluminal coronary angioplasty, transientischemic attacks, stroke, pathologic thrombus formation occuring in theveins of the lower extremities following abdominal, knee and hipsurgery, a risk of pulmonary thromboembolism, or disseminated systemicintravascular coagulatopathy ocurring in vascular systems during septicshock, certain viral infections or cancer.

[0310] The compounds of the formula I and their physiologicallytolerable salts and their prodrugs can be administered to animals,preferably to mammals, and in particular to humans as pharmaceuticalsfor therapy or prophylaxis. They can be administered on their own, or inmixtures with one another or in the form of pharmaceutical preparationswhich permit enteral or parenteral administration.

[0311] The pharmaceuticals can be administered orally, for example inthe form of pills, tablets, lacquered tablets, coated tablets, granules,hard and soft gelatin capsules, solutions, syrups, emulsions,suspensions or aerosol mixtures. Administration, however, can also becarried out rectally, for example in the form of suppositories, orparenterally, for example intravenously, intramuscularly orsubcutaneously, in the form of injection solutions or infusionsolutions, microcapsules, implants or rods, or percutaneously ortopically, for example in the form of ointments, solutions or tinctures,or in other ways, for example in the form of aerosols or nasal sprays.

[0312] The pharmaceutical preparations according to the invention areprepared in a manner known per se and familiar to one skilled in theart, pharmaceutically acceptable inert inorganic and/or organic carriersbeing used in addition to the compound(s) of the formula I and/or its(their) physiologically tolerable salts and/or its (their) prodrugs. Forthe production of pills, tablets, coated tablets and hard gelatincapsules it is possible to use, for example, lactose, corn starch orderivatives thereof, talc, stearic acid or its salts, etc. Carriers forsoft gelatin capsules and suppositories are, for example, fats, waxes,semisolid and liquid polyols, natural or hardened oils, etc. Suitablecarriers for the production of solutions, for example injectionsolutions, or of emulsions or syrups are, for example, water, saline,alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetableoils, etc. Suitable carriers for microcapsules, implants or rods are,for example, copolymers of glycolic acid and lactic acid. Thepharmaceutical preparations normally contain about 0.5% to 90% by weightof the compounds of the formula I and/or their physiologically tolerablesalts and/or their prodrugs. The amount of the active ingredient of theformula I and/or its physiologically tolerable salts and/or its prodrugsin the pharmaceutical preparations normally is from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg.

[0313] In addition to the active ingredients of the formula I and/ortheir physiologically acceptable salts and/or prodrugs and to carriersubstances, the pharmaceutical preparations can contain additives suchas, for example, fillers, disintegrants, binders, lubricants, wettingagents, stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants. They canalso contain two or more compounds of the formula I and/or theirphysiologically tolerable salts and/or their prodrugs. In case apharmaceutical preparation contains two or more compounds of the formulaI the selection of the individual compounds can aim at a specificoverall pharmacological profile of the pharmaceutical preparation. Forexample, a highly potent compound with a shorter duration of action maybe combined with a long-acting compound of lower potency. Theflexibility permitted with respect to the choice of substituents in thecompounds of the formula I allows a great deal of control over thebiological and physicochemical properties of the compounds and thusallows the selection of such desired compounds. Furthermore, in additionto at least one compound of the formula I and/or its physiologicallytolerable salts and/or its prodrugs, the pharmaceutical preparations canalso contain one or more other therapeutically or prophylacticallyactive ingredients.

[0314] As inhibitors of factor Xa and/or factor VIIa the compounds ofthe formula I and their physiologically tolerable salts and theirprodrugs are generally suitable for the therapy and prophylaxis ofconditions in which the activity of factor Xa and/or factor VIIa plays arole or has an undesired extent, or which can favorably be influenced byinhibiting factor Xa and/or factor VIIa or decreasing their activities,or for the prevention, alleviation or cure of which an inhibition offactor Xa and/or factor VIIa or a decrease in their activity is desiredby the physician. As inhibition of factor Xa and/or factor VIIainfluences blood coagulation and fibrinolysis, the compounds of theformula I and their physiologically tolerable salts and their prodrugsare generally suitable for reducing blood clotting, or for the therapyand prophylaxis of conditions in which the activity of the bloodcoagulation system plays a role or has an undesired extent, or which canfavorably be influenced by reducing blood clotting, or for theprevention, alleviation or cure of which a decreased activity of theblood coagulation system is desired by the physician. A specific subjectof the present invention thus are the reduction or inhibition ofunwanted blood clotting, in particular in an individual, byadministering an effective amount of a compound I or a physiologicallytolerable salt or a prodrug thereof, as well as pharmaceuticalpreparations therefor.

[0315] Conditions in which a compound of the formula I can be favorablyused include, for example, cardiovascular disorders, thromboembolicdiseases or complications associated, for example, with infection orsurgery. The compounds of the present invention can also be used toreduce an inflammatory response. Examples of specific disorders for thetreatment or prophylaxis of which the compounds of the formula I can beused are coronary heart disease, myocardial infarction, angina pectoris,vascular restenosis, for example restenosis following angioplasty likePTCA, adult respiratory disstress syndrome, multi-organ failure, strokeand disseminated intravascular clotting disorder. Examples of relatedcomplications associated with surgery are thromboses like deep vein andproximal vein thrombosis which can occur following surgery. In view oftheir pharmacological activity the compounds of the invention canreplace or supplement other anticoagulant agents such as heparin. Theuse of a compound of the invention can result, for example, in a costsaving as compared to other anticoagulants.

[0316] When using the compounds of the formula I the dose can varywithin wide limits and, as is customary and is known to the physician,is to be suited to the individual conditions in each individual case. Itdepends, for example, on the specific compound employed, on the natureand severity of the disease to be treated, on the mode and the scheduleof administration, or on whether an acute or chronic condition istreated or whether prophylaxis is carried out. An appropriate dosage canbe established using clinical approaches well known in the medical art.In general, the daily dose for achieving the desired results in an adultweighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg, (ineach case in mg per kg of body weight). The daily dose can be divided,in particular in the case of the administration of relatively largeamounts, into several, for example 2, 3 or 4, part administrations. Asusual, depending on individual behavior it may be necessary to deviateupwards or downwards from the daily dose indicated.

[0317] A compound of the formula I can also advantageously be used as ananticoagulant outside an individual. For example, an effective amount ofa compound of the invention can be contacted with a freshly drawn bloodsample to prevent coagulation of the blood sample. Further, a compoundof the formula I and its salts can be used for diagnostic purposes, forexample in in vitro diagnoses, and as an auxiliary in biochemicalinvestigations. For example, a compound of the formula I can be used inan assay to identify the presence of factor Xa and/or factor VIIa or toisolate factor Xa and/or factor VIIa in a substantially purified form. Acompound of the invention can be labeled with, for example, aradioisotope, and the labeled compound bound to factor Xa and/or factorVIIa is then detected using a routine method useful for detecting theparticular label. Thus, a compound of the formula I or a salt thereofcan be used as a probe to detect the location or amount of factor Xaand/or factor VIIa activity in vivo, in vitro or ex vivo.

[0318] Furthermore, the compounds of the formula I can be used assynthesis intermediates for the preparation of other compounds, inparticular of other pharmaceutical active ingredients, which areobtainable from the compounds of the formula I, for example byintroduction of substituents or modification of functional groups.

[0319] It is understood that changes that do not substantially affectthe activity of the various embodiments of this invention are includedwithin the invention disclosed herein. Thus, the following examples areintended to illustrate but not limit the present invention.

EXAMPLES

[0320] Abbreviations used: tert-Butyl tBu Dichloromethane DCM Diethylazodicarboxylate DEAD Diisopropyl azodicarboxylate DIADN,N′-Diisopropylcarbodiimide DIC N,N-Diisopropyl-N-ethylamine DIEAN,N-Dimethylformamide DMF Dimethylsulfoxide DMSOO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- HATUtetramethyluronium-hexafluorophosphate 1-Hydroxy-7-azabenzotriazole HOAtN-Ethylmorpholine NEM Methanol MeOH Tetrahydrofuran THF Trifluoroaceticacid TFA

[0321] When in the final step of the synthesis of a compound an acidsuch as trifluoroacetic acid or acetic acid was used, for example whentrifluoroacetic acid was employed to remove a tert-butyl group or when acompound was purified by chromatography using an eluent which containedsuch an acid, in some cases, depending on the work-up procedure, forexample the details of a freeze-drying process, the compound wasobtained partially or completely in the form of a salt of the acid used,for example in the form of the acetic acid salt or trifluoroacetic acidsalt or hydrochloric acid salt.

Example 1(S)-(1-Carbamimidoyl-piperidin-4-yl)-{3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzoylamino}-aceticAcid Methyl Ester

[0322]

[0323] (a) 3,5-Dihydroxy-benzoic Acid Allyl Ester

[0324] To 1.5 g of 3,5-dihydroxybenzoic acid in screw-capped vial wasadded 10 g of allyl alcohol and the vial was closed and cooled to −20°C. To the cold contents of the reaction vial was added 5 mL oftrimethylsilyl chloride via syringe through a septum. The reaction vialwas allowed to warm to room temperature and agitated for 16 hours. Thevial was opened carefully and its contents transferred to around-bottomed flask. The solvent was removed under reduced pressure andthe residual solid was dried under reduced pressure over potassiumhydroxide pellets for 12 h. The semisolid product was used in thesubsequent synthetic steps without further purification. The product wasanalyzed by HPLC and had a retention time of 3.65 on 5 cm C₁₈ reversedphase column with flow rate of 2.5 mL/min of pure acetonitrile (forsolvent A) and 0.1% aqueous trifluroacetic acid (for solvent B). Theproduct was characterized by ¹H NMR (DMSO-d₆, 350 MHz): δ=6.87 (s, 2H,aromatic); 6.44 (s, 1H, aromatic); 5.85-5.96 (m, 1H); 5.16-5.33 (m, 2H);4.65-4.67(dd, 2H).

[0325] (b) 300 mg of (2′-chloro)-Chlorotrityl-polystyrene resin (0.39mmols; loading 1.3 mmol/g Cl) was treated with 4 mL of dichloroethaneand the resin was left to swell at room temperature for 30 minutes. Thesolvent was removed by filtration and the resin was treated with asolution of 227 mg of 3,5-dihydroxy-benzoic acid allyl ester and 0.4 mLof DIEA in 5 mL anhydrous dichloromethane. The resin suspension wasagitated for 3 to 4 h at 600 C. The resin was washed with DMF (3 times),DCM (5 times) and DMF (5 times) and used in next step.

[0326] (c) The resin from step (b) was washed with anhydrous THF (3times) and suspended in 4 mL of anhydrous THF containing 511 mg oftriphenylphosphine and 745 mg of 2,4-dichlorophenethyl alcohol. Thesuspension was cooled to −15° C. and 0.384 mL of DIAD was added. Theresin suspension was agitated at room temperature for 12 h. The solventwas removed by filtration and the resin was washed with THF (9 times),DMF (5 times), DCM (5 times). The resin was used in the next step.

[0327] (d) The resin from step (c) was suspended in DCM and 365 mg of1,3-dimethylbarbituric acid was added in the presence of 45 mg of Pd(0)(PPh₃)₄ under argon. The resin suspension was agitated for one hourat room temperature. The solvent was removed by filtration and the resinwas washed with DCM and dried.

[0328] (e) Dried resin from step (d) was washed with DMF and suspendedin 3 mL DMF containing 265 mg of HOAt and 0.302 mL of DIC. The resin wasagitated for 5 minutes and 613 mg of(S)-amino-[1-(tert-butoxycarbonylamino-imino-methyl)-piperidin-4-yl]-aceticacid methyl ester was added. The resin suspension was agitated for 12 h.The resin was washed with DMF and DCM and dried under reduced pressurefor 6-8 h.

[0329] (f) The dried resin from step (e) was suspended in DCM containing50% TFA and agitated at room temperature for 45 minutes. The resinsuspension was filtered, washed with DCM: TFA (1:1) and the washingscombined with the cleavage filtrate. The cleavage solution was driedunder reduced pressure. The solid product was lyophilized from 30%aqueous acetonitrile and crude product purified by HPLC on reverse phaseC₁₈ column.

[0330] Fractions containing the desired product were pooled andlyophilized to give(S)-(1-Carbamimidoyl-piperidin-4-yl)-{3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzoylamino}-aceticacid methyl ester as a white solid. The product was identified by LC/MSto give m/e=523 (M+H)⁺.

Example 24-Bromo-N-(1-carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzamide

[0331]

[0332] (a) 4-Bromo-3,5-dihydroxy-benzoic Acid Allyl Ester

[0333] This compound was prepared analogously to 3,5-Dihydroxy-benzoicacid allyl ester [Example 1 (a)], however 4-bromo-3,5-dihydroxybenzoicacid was used instead of 3,5-dihydroxybenzoic acid. ¹H NMR (DMSO-d₆, 350MHz): δ=7.04 (s, 2H, aromatic); 5.97-6.06 (m, 1H); 5.25-5.40 (m, 2H);4.73-4.75(dd, 2H).

[0334] (b) The title compound was synthesized analogously to Example 1,steps (b)-(f) with the following differences:

[0335] In step (b) 4-Bromo-3,5-dihydroxy-benzoic acid allyl ester wasused instead of 3,5-dihydroxy-benzoic acid allyl ester;

[0336] In step (e)[(4-aminomethyl-piperidin-1-yl)-imino-methyl]-carbamic acid tert-butylester was used instead of(S)-amino-[1-(tert-butoxycarbonylamino-imino-methyl)-piperidin-4-yl]-aceticacid methyl ester. The final product was purified by HPLC andcharacterized by LC/MS to give m/e=543.3 (M+H)⁺.

Example 3N-(1-Carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-4-methyl-benzamide

[0337]

[0338] (a) 3,5-dihydroxy-4-methylbenzoic Acid Allyl Ester

[0339] This compound was prepared analogously to 3,5-Dihydroxy-benzoicacid allyl ester [Example 1 (a)], however 3,5-dihydroxy-4-methylbenzoicacid was used instead of 3,5dihydroxybenzoic acid.

[0340] (b) The title compound was synthesized analogously to Example 2,with the following difference:

[0341] 3,5-dihydroxy-4-methyl-benzoic acid allyl ester was used insteadof 4-Bromo-3,5-dihydroxy-benzoic acid allyl ester. The final product waspurified by HPLC and characterized by LC/MS to give m/e=478.8 (M+H)⁺.

[0342] Analogously to the above examples the following example compoundswere prepared by similar procedures and characterized by LC/MS: ExampleStructure MWt (M + H)⁺ 4

464.13 465.3 5

536.15 537.3 6

564.10 565.3 7

513.22 514.3 8

523.10 524 9

411.23 412 10

475.11 476

Example 11N-(1-Carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

[0343]

[0344] (a) 3-Hydroxy-4-methoxy-benzoic Acid Methyl Ester

[0345] 10 mL of thionyl chloride was added to 250 mL of methanol at 0°C. The solution was stirred for 10 minutes and 25 g of3-hydroxy-4-methoxybenzoic acid were added. The reaction was stirred for16 h at room temperature then heated to 50° C. for 3 h. The solventswere removed under reduced pressure. The residue was used directly inthe next step.

[0346] (b) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic AcidMethyl Ester

[0347] 20 g of triphenylphosphine and 10 g of3-Hydroxy-4-methoxy-benzoic acid methyl ester were dissolved in 200 mLof anhydrous THF. The solution was cooled to ⁰° C. to 10° C. and asolution of 11.4 mL DEAD in 30 mL anhydrous THF was added dropwise over20 min. The reaction was warmed to room temperature and stirred for 45min. A solution of 11.3 mL 2-(2,4-Dichlorophenyl)-ethanol in 10 mLanhydrous THF was added with cooling. The reaction was stirred at roomtemperature for 16 h, then the solvents were removed under reducedpressure. The residue was treated with n-heptane:ethyl acetate/1:1. Thefiltrate was dried under reduced pressure. The product was purified bysilica gel chromatography, eluting with n-heptane:ethyl acetate/4:1,then n-heptane:ethyl acetate/3:1. Yield 17 g.

[0348] (c) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic Acid

[0349] 17 g of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acidmethyl ester was dissolved in 200 mL of methanol:water/3:1. 4.1 g oflithium hydroxide monohydrate was added to the solution, and thereaction was stirred at room temperature for 16 h then at 90° C. for 2h. The solution was cooled to room temperature, then acidified withhalf-concentrated hydrochloric acid. The solvents were removed underreduced pressure and the residue was washed twice with warm water toremove salts.

[0350] (d) A solution of 100 mg3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml DMF wasactivated by the addition of 53 mg carbonyldiimidazole. After stirringfor 2 h at RT 90 mg of 4-Aminomethyl-piperidine-1-carboxamidinehydrochloride and 2 ml DMSO were added and the mixture was stirredovernight. Subsequent dilution with 3 ml water and filtration through achem elut® cartridge, eluting with ethyl acetate yielded afterconcentration under reduced pressure a white solid. Purification bypreparative HPLC (C₁₈ reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) and lyophilisation afforded 30 mg (20%) of thetitle compound as a white powder. MS (ESI+) m/e 479.3 (M+H) chloropattern.

Example 123-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[1-(1-imino-ethyl)-piperidin-4-ylmethyl]-4-methyl-benzamide;Compound with Trifluoro-Acetic Acid

[0351]

[0352] 50 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acidand 58.9 mg of C-[1-(1-imino-ethyl)-piperidin-4-yl]-methylaminedi-trifluoroacetic acid salt were dissolved in 5 ml of DMF. Aftercooling to 0° C. 64.3 mg of HATU and 70.8 mg of NEM were added. Themixture was stirred at 0° C. for 2 hours and at room temperature for 3hours. The solvent was removed under reduced pressure and the residuewas purified by preparative HPLC (C18 reverse phase column) (gradientacetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to0:100). The fractions containing the product were evaporated andlyophilized. Yield: 48 mg (54%), MS: 462.2/464.3 (M+H)⁺.

Example 13N-(1-Carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzamide;Compound with Trifluoro-Acetic Acid

[0353]

[0354] 50 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acidand 35.2 mg of 4-aminomethyl-piperidine-1-carboxamidine dihydrochloridewere dissolved in 5 ml of DMF. After cooling to 0° C. 64.3 mg of HATUand 70.8 mg of NEM were added. The mixture was stirred at 0° C. for 2hours and at room temperature for 3 hours. The solvent was removed underreduced pressure and the residue was purified by preparative HPLC (C₁₈reverse phase column) (gradient acetonitrile water (containing 0.1%trifluoro-acetic acid) 90:10 to 0:100). The fractions containing theproduct were evaporated and lyophilized.

[0355] Yield: 45 mg (51%), MS: 463.3/465.3 (M+H)⁺.

Example 14{Amino-[4-({3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-methyl)-piperidin-1-yl]-methylene}-carbamicAcid Benzyl Ester

[0356]

[0357] 97 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acidand 124.3 mg of[Amino-(4-aminomethyl-piperidin-1-yl)-methylene]-carbamic acid benzylester trifluoroacetic acid salt were dissolved in 5 ml of DMF. Aftercooling to ⁰° C. 136 mg of HATU and 106 mg of NEM were added. Themixture was stirred at 0° C. for 2 hours and at room temperature for 3hours. The solvent was removed under reduced pressure and the residuewas purified by preparative HPLC (C₁₈ reverse phase column) (gradientacetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to0:100). The fractions containing the product were evaporated andlyophilized.

[0358] Yield: 146 mg (79.5%), MS: 597.3/599.3 (M+H)⁺.

[0359] Pharmacological Testing

[0360] The ability of the compounds of the formula I to inhibit factorXa or factor VIIa or other enzymes like thrombin, plasmin, or trypsincan be assessed by determining the concentration of the compound of theformula I that inhibits enzyme activity by 50%, i.e. the IC₅₀ value,which is related to the inhibition constant Ki. Purified enzymes areused in chromogenic assays. The concentration of inhibitor that causes a50% decrease in the rate of substrate hydrolysis is determined by linearregression after plotting the relative rates of hydrolysis (compared tothe uninhibited control) versus the log of the concentration of thecompound of formula I. For calculating the inhibition constant Ki, theIC₅₀ value is corrected for competition with substrate using the formula

Ki=IC ₅₀/{1+(substrate concentration/Km)}

[0361] wherein Km is the Michaelis-Menten constant (Chen and Prusoff,Biochem. Pharmacol. 22 (1973), 3099-3108; I. H. Segal, Enzyme Kinetics,1975, John Wiley & Sons, New York, 100-125; which are incorporatedherein by reference).

[0362] a) Factor Xa Assay

[0363] In the assay for determining the inhibition of factor Xa activityTBS-PEG buffer (50 mM Tris-HCl, pH 7.8, 200 mM NaCl, 0.05% (w/v)PEG-8000, 0.02% (w/v) NaN₃) was used. The IC₅₀ was determined bycombining in appropriate wells of a Costar half-area microtiter plate 25μl human factor Xa (Enzyme Research Laboratories, Inc.; South Bend,Ind.) in TBS-PEG; 40 μl 10% (v/v) DMSO in TBS-PEG (uninhibited control)or various concentrations of the compound to be tested diluted in 10%(v/v) DMSO in TBS-PEG; and substrate S-2765(N(α)-benzyloxycarbonyl-D-Arg-Gly-L-Arg-p-nitroanilide; Kabi Pharmacia,Inc.; Franklin, Ohio) in TBS-PEG.

[0364] The assay was performed by pre-incubating the compound of formulaI plus enzyme for 10 min. Then the assay was initiated by addingsubstrate to obtain a final volume of 100 μl. The initial velocity ofchromogenic substrate hydrolysis was measured by the change inabsorbance at 405 nm using a Bio-tek Instruments kinetic plate reader(Ceres UV900HDi) at 25° C. during the linear portion of the time course(usually 1.5 min after addition of substrate). The enzyme concentrationwas 0.5 nM and substrate concentration was 140 μM.

[0365] b) Factor VIIa Assay

[0366] The inhibitory activity towards factor VIIa/tissue factoractivity was determined using a chromogenic assay essentially asdescribed previously (J. A. Ostrem et al., Biochemistry 37 (1998)1053-1059 which is incorporated herein by reference). Kinetic assayswere conducted at 25° C. in half-area microtiter plates (Costar Corp.,Cambridge, Mass.) using a kinetic plate reader (Molecular DevicesSpectramax 250). A typical assay consisted of 25 μl human factor VIIaand TF (5 nM and 10 nM, respective final concentration) combined with 40μl of inhibitor dilutions in 10% DMSO/TBS-PEG buffer (50 mM Tris, 15 mMNaCl, 5 mM CaCl₂, 0.05% PEG 8000, pH 8.15). Following a 15 minutepreincubation period, the assay was initiated by the addition of 35 μlof the chromogenic substrate S-2288 (D-Ile-Pro-Arg-p-nitroanilide,Pharmacia Hepar Inc., 500 μM final concentration).

[0367] The following test results (inhibition constants Ki (FXa) forinhibition of factor Xa) were obtained:

[0368] Example 1: Ki(FXa) 2.116 micromolar

[0369] Example 2: Ki(FXa) 0.0137 micromolar

[0370] Example 3: Ki(FXa) 0.0585 micromolar

[0371] Example 4: Ki(FXa) 0.4635 micromolar

[0372] Example 6: Ki(FXa) 2.280 micromolar

[0373] Example 11: Ki(FXa) 0.189 micromolar

[0374] Example 12: Ki(FXa) 0.14 micromolar

[0375] Example 13: Ki(FXa) 0.173 micromolar

[0376] Example 14: Ki(FXa) 5.077 micromolar (Prodrug)

1. A compound of the formula I,

wherein R₀ is
 1. phenyl, wherein phenyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R² or
 2. a mono- orbicyclic 5- to 10-membered heteroaryl containing one or two nitrogenatoms as ring heteroatoms, wherein heteroaryl is unsubstituted or mono-,di- or trisubstituted independently of one another by R², R²is
 1. —NO₂,2. halogen,
 3. —CN,
 4. —OH,
 5. —NH₂,
 6. (C₁-C₈)-alkyloxy-, whereinalkyloxy is unsubstituted or mono-, di- or trisubstituted independentlyof one another by halogen, amino group, hydroxy group or methoxy group,or
 7. —(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by halogen, amino group,hydroxy group or methoxy group, Q and Q′ are independently of oneanother identical or different and are a direct bond, —O—, —S—, —NR¹⁰—,—C(O)NR¹⁰—, —NR¹⁰C(O)—, —S(O)—, —SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰— oder—C(O)—; R¹⁰ is hydrogen atom or (C₁-C₄)-alkyl-, X is
 1. a direct bond,2. (C₁-C₆)-alkylen, wherein alkylen is unsubstituted or mono-, di- ortrisubstituted independently of one another by halogen, amino group or ahydroxy group,
 3. (C₃-C₆)-cycloalkylen, wherein cycloalkylen isunsubstituted or mono-, di- or trisubstituted independently of oneanother by halogen, amino group or a hydroxy group, provided that atleast one of Q, X and Q′ is not a direct bond, D is an atom out of thegroup carbon, oxygen, sulfur and nitrogen, the substructure of formulaIII

is
 1. a mono- or bicyclic 5- to 10-membered carbocyclic aryl group,wherein said 5- to 10-membered carbocyclic aryl group is unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹, 2.phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹,
 3. a mono- or bicyclic 5-to10-membered heterocyclic group (Het), containing one or more heteroatomsas ring heteroatoms, such as nitrogen, sulfur or oxygen, wherein saidHet group is unsubstituted or mono-, di- or trisubstituted independentlyof one another by R¹, or
 4. pyridyl, wherein pyridyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹, R¹is
 1. halogen,
 2. —NO₂,
 3. —CN,
 4. R¹¹R¹²N—, wherein R¹¹R¹²independently of one another are hydrogen atom, (C₁-C₄)-alkyl- or(C₁-C₆)-acyl-,
 5. (C₁-C₈)-alkylamino-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, 6.—OH,
 7. —SO₂—NH₂,
 8. (C₁-C₈)-alkyloxy-, wherein alkyl is unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹³, 9.(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,
 10. (C₁-C₈)-alkyl-,wherein alkyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³, 11.hydroxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, 12.(C₁-C₈)-alkyloxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,
 13. (C₁-C₈)-alkylsulfonyl-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³, or
 14. —C(O)—NR¹⁴R¹⁵, wherein R⁴R¹⁵ independently of oneanother are hydrogen atom or (C₁-C₄)-alkyl-, or two R¹ residues bondedto adjacent ring carbon atoms together with the carbon atoms to whichthey are bonded form an aromatic ring condensed to the ring depicted informula I, where the ring formed by the two R¹ residues is unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹³, R¹¹and R¹² together with the nitrogen atom to which they are bonded form asaturated or unsaturated 5- to 6-membered monocyclic heterocyclic ringwhich in addition to the nitrogen atom carrying R¹¹ and R¹² can containone or two identical or different ring heteroatoms chosen from oxygen,sulfur and nitrogen, and in which one or two of the ring carbon atomscan be substituted by oxo to form —C(O)— residue(s), R¹³ is
 1. halogen,2. —NO₂,
 3. —CN,
 4. —OH,
 5. (C₁-C₈)-alkyl-,
 6. (C₁-C₈)-alkyloxy-, 7.—CF₃ or
 8. —NH₂, V is a residue of the formulae IIa, IIb, IIc, IId, IIeor IIf,

wherein L is is a direct bond or (C₁-C₃)-alkylene, wherein alkylene isunsubstituted or mono-, di- or trisubstituted independently of oneanother by A, A is
 1. hydrogen atom,
 2. —C(O)—OH, 3.—C(O)—O—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di- ortri-substituted independently of one another by —OH, —NH₂ or—(C₁-C₄)-alkoxy,
 4. —C(O)—NR⁴R⁵,
 5. (C₁-C₄)-alkyl-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by —OH, —NH₂ or —(C₁-C₄)-alkoxy,
 6. —SO₂—NH₂ or
 7. —SO₂—CH₃, Uis —NH₂, (C₁-C₄)-alkyl-,—NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(C₁-C₄)-alkyl-aryl, M is hydrogen atom, (C₁-C₃)-alkyl- or—OH, R⁴ and R⁵ are independently of one another identical or differentand are
 1. hydrogen atom,
 2. (C₁-C₁₂)-alkyl-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³ as defined above,
 3. (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-,wherein alkyl and aryl are unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³ as defined above,
 4. (C₆-C₁₄)-aryl-,wherein aryl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³ as defined above,
 5. Het-, whereinHet- is unsubstituted or mono-, di- or trisubstituted independently ofone another by R¹³ as defined above, or
 6. Het-(C₁-C₄)-alkyl-, whereinalkyl and Het- are unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³ as defined above, or R⁴ and R⁵together with the nitrogen atom to which they are bonded form asaturated 3- to 8-membered monocyclic heterocyclic ring which inaddition to the nitrogen atom carrying R⁴ and R⁵ can contain one or twoidentical or different ring heteroatoms chosen from oxygen, sulfur andnitrogen; in all its stereoisomeric forms and mixtures thereof in anyratio, and its physiologically tolerable salts.
 2. A compound of formulaI as claimed in claim 1, wherein R₀ is phenyl, wherein phenyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R², or pyridyl, wherein pyridyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R², R² is
 1. —NO₂,2. halogen,
 3. —CN,
 4. —OH,
 5. —NH₂,
 6. (C₁-C₄)-alkyloxy-, whereinalkyloxy is unsubstituted or mono-, di- or trisubstituted independentlyof one another by halogen, amino group, hydroxy group or methoxy group,or
 7. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by halogen, amino group,hydroxy group or methoxy group, Q, Q′, X, R¹, R¹¹ and R¹² are as definedin claim 1, D is an atom out of the group carbon and nitrogen, thesubstructure of formula III is
 1. phenyl, wherein phenyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹, or
 2. pyridyl, wherein pyridyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹, R¹³ is 1.halogen,
 2. —NO₂,
 3. —CN,
 4. —OH,
 5. (C₁-C₄)-alkyl-, 6.(C₁-C₄)-alkyloxy-,
 7. —CF₃ or
 8. —NH₂, R₁₀ is hydrogen atom or methyl, Vis a fragment of the formula IIa, IIb, IIc, IId, IIe or IIf as definedabove, wherein L, U, M, R⁴ and R⁵ are as defined in claim 1, and A is 1.hydrogen atom,
 2. —C(O)—OH,
 3. —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl isunsubstituted or mono-, di- or tri-substituted independently of oneanother by —OH, —NH₂ or —(C₁-C₄)-alkoxy,
 4. —C(O)—NR⁴R⁵ or 5.(C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by —OH, —NH₂ or—(C₁-C₄)-alkoxy.
 3. A compound of the formula I as claimed in claim 1 or2, wherein R₀ is phenyl, wherein phenyl is mono-, di- or trisubstitutedindependently of one another by R², or pyridyl, wherein pyridyl ismono-, di- or trisubstituted independently of one another by R², R²is 1.—NH₂,
 2. halogen,
 3. —CN,
 4. —OH,
 5. (C₁-C₄)-alkyloxy-, wherein alkyloxyis unsubstituted or substituted by an amino group, or
 6. —(C₁-C₄)-alkyl,wherein alkyl is unsubstituted or substituted by an amino group, Q andQ′ are independently of one another identical or different and are adirect bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—; or —SO₂—NR¹⁰—; Xis
 1. a direct bond or
 2. (C₁-C₄)-alkylen, wherein alkylen isunsubstituted or mono-, di- or trisubstituted independently of oneanother by halogen, amino group or a hydroxy group, D is an atom out ofthe group carbon and nitrogen, the substructure of formula III is phenylor pyridyl, wherein phenyl and pyridyl are unsubstituted or mono-, di-or trisubstituted independently of one another by R¹, R¹ is
 1. halogen,2. —NO₂,
 3. —CN,
 4. —NH₂,
 5. (C₁-C₄)-alkylamino-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,
 6. —OH,
 7. —SO₂—NH₂,
 8. (C₁-C₄)-alkyloxy-, wherein alkylis unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,
 9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, 10.(C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³, 11.(C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,
 12. —C(O)—NR¹⁴R¹⁵,wherein R¹⁴R¹⁵ independently of one another are hydrogen atom or(C₁-C₄)-alkyl-,
 13. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above,or
 14. —NR⁴R⁵, R¹³ is
 1. halogen,
 2. —NO₂,
 3. —CN,
 4. —OH, 5.(C₁-C₄)-alkyl-,
 6. (C₁-C₄)-alkyloxy-,
 7. —CF₃ or
 8. —NH₂, R₁₀ ishydrogen atom or methyl, V is a fragment of the formula IIa, IIb, IIc,IId, IIe or IIf as defined above, wherein L is a direct bond or(C₁-C₃)-alkylen-, A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,—C(O)—NR⁴R⁵ or (C₁-C₄)-alkyl-, U is —NH₂, methyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl, M is hydrogen atom,(C₁-C₃)-alkyl- or —OH, and R⁴ and R⁵ are independently of one anotherhydrogen atom or (C₁-C₄)-alkyl-.
 4. A compound of formula I as claimedin one or more of claims 1 to 3, wherein R₀ is phenyl or pyridyl,wherein phenyl and pyridyl independently from one another are mono-, di-or trisubstituted independently of one another by R², R² is
 1. halogen,2. —CN,
 3. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted orsubstituted by halogen or an amino group, or
 4. —(C₁-C₄)-alkyl, whereinalkyl is unsubstituted or substituted by an amino group or halogen, Qand Q′ are independently of one another identical or different and are adirect bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—; or —SO₂—NR¹⁰—; Xis —(C₁-C₃)-alkylen-, wherein alkylen is unsubstituted or mono-, di- ortrisubstituted independently of one another by halogen, amino group orhydroxy group, D is the atom carbon, the substructure of formula III isphenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹, R¹ is
 1. halogen,
 2. —NO₂,
 3. —CN,4. —NH₂,
 5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, 6.—OH,
 7. —SO₂—NH₂,
 8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹³, 9.(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,
 10. (C₁-C₄)-alkyl-,wherein alkyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³,
 11. (C₁-C₄)-alkylsulfonyl-, whereinalkyl is unsubstituted or mono-, di- or trisubstituted independently ofone another by R¹³,
 12. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently ofone another are hydrogen atom or (C₁-C₄)-alkyl-,
 13. R¹¹R¹²N—, whereinR¹¹ and R¹² are as defined above, or
 14. —NR⁴R⁵, R¹³ is
 1. halogen, 2.—CF₃,
 3. —NH₂,
 4. —OH,
 5. (C₁-C₄)-alkyl- or
 6. (C₁-C₄)-alkyloxy-, R₁₀ ishydrogen atom, and V is a fragment of the formula IIa, IIb, IIc or IIdas defined above, wherein L is a direct bond or (C₁-C₂)-alkylen-, A ishydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵ or(C₁-C₄)-alkyl, U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or—NH—C(O)—O—(CH₂)-phenyl, M is hydrogen atom or (C₁-C₃)-alkyl-, and R⁴and R⁵ are independently of one another hydrogen atom or methyl.
 5. Acompound of formula I as claimed in one or more of claims 1 to 4,wherein R₀ is phenyl, wherein phenyl is mono-, di- or trisubstitutedindependently of one another by R², R² is
 1. halogen, 2.(C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted or substituted byhalogen or an amino group, or
 3. —(C₁-C₄)-alkyl, wherein alkyl isunsubstituted or substituted by an amino group or halogen, Q and Q′ areindependently of one another identical or different and are a directbond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—; or —SO₂—NR¹⁰—; X is—(C₁-C₃)-alkylen-, D is the atom carbon, the substructure of formula IIIis phenyl, wherein phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹, R¹ is
 1. halogen, 2.—NO₂,
 3. —CN,
 4. —NH₂,
 5. (C₁-C₄)-alkylamino-, wherein alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,
 6. —OH,
 7. —SO₂—NH₂,
 8. (C₁-C₄)-alkyloxy-, wherein alkylis unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³,
 9. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, 10.(C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³,
 11. —C(O)—NR⁴R⁵,wherein R⁴R¹⁵ independently of one another are hydrogen atom or(C₁-C₂)-alkyl-,
 12. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above,or
 13. —NR⁴R⁵, R¹³ is
 1. halogen,
 2. —CF₃,
 3. —NH₂,
 4. —OH, 5.(C₁-C₄)-alkyl- or
 6. (C₁-C₄)-alkyloxy-, R₁₀ is hydrogen atom, and V is afragment of the formula IIa, IIb, IIc or IId as defined above, wherein Lis a direct bond or (C₁-C₂)-alkylen-, A is hydrogen atom, —C(O)—OH,—C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵ or —(C₁-C₄)-alkyl, U is —NH₂, methyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl, M is hydrogen atomor methyl, and R⁴ and R⁵ are independently of one another hydrogen atomor methyl.
 6. A compound of formula I as claimed in one or more ofclaims 1 to 5, wherein R₀ is phenyl, wherein phenyl is disubstitutedindependently of one another by R², R is
 1. halogen, 2.(C₁-C₂)-alkyloxy-, wherein alkyloxy is unsubstituted or substituted byan amino group, or
 3. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted orsubstituted by an amino group, Q and Q′ are independently of one anotheridentical or different and are a direct bond or —O—, X is —CH₂—CH₂—, Dis the atom carbon, the substructure of formula III is phenyl, whereinphenyl is unsubstituted or mono-, di- or trisubstituted independently ofone another by R¹, R¹ is
 1. halogen,
 2. —OH,
 3. —NH₂,
 4. —C(O)—NR¹⁴R⁵,wherein R¹⁴R¹⁵ independently of one another are hydrogen atom or(C₁-C₂)-alkyl-,
 5. (C₁-C₃)-alkyloxy-, wherein alkyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³, or 6.(C₁-C₃)-alkyl-, wherein alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³, R¹³ is fluorine orchlorine, R₁₀ is hydrogen atom, and V is a fragment of the formula IIa,IIb, IIc or IId as defined above, wherein L is a direct bond or(C₁-C₂)-alkylen-, A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,—C(O)—NR⁴R⁵ or —(C₁-C₄)-alkyl, U is —NH₂, methyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl, M is hydrogen atom,and R⁴ and R⁵ are independently of one another hydrogen atom or methyl.7. A process for the preparation of a compound of the formula I asclaimed in one or more of claims 1 to 6, comprises a) linking a buildingblock of the formula XI,

in which Ro, Q, Q′ and X, are as in claims 1 to 6, and R^(1′), R^(1″),R^(1′″), R^(1″″), are hydrogen atom or as R¹ as defined in claims 1 to6, but where in R₀, Q, R¹ Q′ and X functional groups can also be presentin protected form or in the form of precursor groups, and Y is anucleophilically substituable leaving group or a hydroxyl group, isreacted with a fragment of the formula III H—NR₁₀—V  (XII) in which R₁₀and V are as defined in claims 1 to 6, but where in R₁₀ and V functionalgroups can also be present in protected form or in the form of precursorgroups, or b) by coupling of a fragment of the formula XIII withfragment XII, R₀—Q—X—Q′—W—C(O)—Y  (XIII) in which R₀, Q, Q′ and X, areas in claims 1 to 6, W is the substructure of formula III, but where inR₀, Q, Q′, W and X functional groups can also be present in protectedform or in the form of precursor groups, and Y is a nucleophilicallysubstituable leaving group or a hydroxyl group or a hydroxy group may beattached to a polystyrene resin.
 8. A pharmaceutical preparation,comprising at least one compound of the formula I as claimed in one ormore of claims 1 to 6 and/or its physiologically tolerable salts and apharmaceutically acceptable carrier.
 9. The use of a compound of theformula I as claimed in one or more of claims 1 to 6 and/or theirphysiologically tolerable salts and/or their prodrugs for the productionof pharmaceuticals for inhibition of factor Xa and/or factor VIIa or forinfluencing blood coagulation or fibrinolysis.
 10. The use as claimed inclaim 9 for influencing blood coagulation, inflammatory response,fibrinolysis, cardiovascular disorders, thromboembolic diseases,restenoses, abnormal thrombus formation, acute myocardial infarction,unstable angina, acute vessel closure associated with thrombolytictherapy, thromboembolism, percutaneous, pathologic thrombus formationoccuring in the veins of the lower extremities following abdominal, kneeand hip surgery, transluminal coronary angioplasty, transient ischemicattacks, stroke a risk of pulmonary thromboembolism, certain viralinfections or cancer, intravascular coagulatopathy ocurring in vascularsystems during septic shock, coronary heart disease, myocardialinfarction, angina pectoris, vascular restenosis, for example restenosisfollowing angioplasty like PTCA, adult respiratory disstress syndrome,multi-organ failure, stroke and disseminated intravascular clottingdisorder, thromboses like deep vein and proximal vein thrombosis whichcan occur following surgery.
 11. A prodrug of the compound of theformula I as claimed in claims 1 to 6, preferably a (C₁-C₆)-acyl or(C₁-C₆)-alkyloxycarbonyl prodrugs of the compound of the formula I asclaimed in claims 1 to 6.